Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial
Authors: Andrew W Horne, Stephen Tong, Catherine A Moakes, Lee J Middleton, W Colin Duncan, Ben W Mol, Lucy H R Whitaker, Davor Jurkovic, Arri Coomarasamy, Natalie Nunes, Tom Holland, Fiona Clarke, Ann M Doust, Jane P Daniels, Amna Ahmed, Hazel Alexander, Sonal Anderson, Rita Arya, Gabriel Awadzi, Miriam Baumgarten, Renee Behrens, Kelly Bingham, Cecilia Bottomley, Tom Bourne, Ying Cheong, Justin Chu, Frances Collins, Janet Cresswell, Sangeetha Devarajan, Punukollu Durgadevi, Umo Esen, Radwan Faraj, Priscilla Fernandez, Joanne Fletcher, Benjamin Galea, Ingrid Granne, Pratima Gupta, Susannah Hogg, Shahzya Huda, Sucheta Iyengar, Ngozi Izuwah-Njoku, Feras Izzat, Thangamma Katimada-Annaiah, Pinky Khatri, Kathleen King, Emma Kirk, Chitra Kumar, Geeta Kumar, Louise Linsell, Mayank Madhra, Krupa Madhvani, Rebecca McKay, Fouzia Memon, Usha Menon, Shruti Mohan, Scott Nelson, Helena Nik, Hema Nosib, Jerry Oghoetuoma, Abigail Oliver, Binita Pande, Mamta Pathak, Alexandra Peace-Gadsby, Janaki Putran, Sundararajah Raajkumar, Vinita Raheja, Malar Raja, Gautam Raje, Sandhya Rao, Penny Robshaw, Faye Rodger, Jackie Ross, Sherif Saleh, Sridevi Sankharan, Mona Sharma, Sanjay Sinha, Kate Stewart, Lauren Sutherland, Rebecca Thompson, Sakunthala Tirumuru, Nicola Watson, Sandra Watson, Ursula Winters, Catherine Wykes
Journal: The Lancet (2023)

Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy.We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930.Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group.In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions.National Institute of Health Research.